Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 52, Pages 18968-18973Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0507902102
Keywords
CCL6; DNA microarray; gene profiling; IL-3; Max
Categories
Funding
- NCI NIH HHS [R01 CA078259, CA078259, CA105033, R01 CA105033] Funding Source: Medline
- NICHD NIH HHS [T32 HD042987, T32HD 042987] Funding Source: Medline
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In addition to its role in cancer, the c-Myc oncoprotein controls many normal cellular processes as a consequence of its function as a basic helix-loop-helix leucine zipper transcription factor. Determining which of the myriad genes under c-Myc control are relevant for these various roles is thus a major challenge. mt-mc1 is a direct c-Myc target gene whose overexpression recapitulates multiple c-Myc phenotypes, including transformation. Using transcriptional profiling, we now show that MT-MC1-overexpressing myeloid cells misregulate a total of 47 distinct transcripts, a large proportion of which are involved in signal transduction and/or cancer. Analysis of these genes reveals a consensus promoter structure consisting of multiple, often closely spaced c-Myc binding sites and three additional Wilm's tumor and Egr1-like motifs. More than one-third of MT-MC1 target genes are also clustered on six cancer-associated chromosomal loci. Most surprisingly, all of the transcripts examined also are regulated by c-Myc. Finally, an estrogen receptor-MT-MC1 fusion protein was used to establish that all examined transcripts were regulated directly by the chimeric protein. Our results thus indicate that MT-MC1 target genes largely comprise a subset of those regulated by c-Myc. We propose that the properties imparted by MT-MC1 are the result of its control of a small and select c-Myc target gene population.
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